Influenza virus normally is associated with acute infections of the repiratory tract. If mice are allowed to recover from an infection with influenza A2/Jap 305 (H2N2) infectious virus is no longer excreted. If these mice are subsequently challenged with influenza A2/Aichi (H3N2), virus possessing hemagglutinin H2 can once again be recovered. Presumably A2/Jap 305 virus had established persistent infection. It is postulated that the latter was mediated by defective-interfering (DI) particles or other forms of incomplete virus. Superinfection with the related sub-type may then have acted as helper virus and supplied the missing gene products, thus allowing replication of the persistent virus. This proposed mechanism will be investigated in detail both in the mouse and in cell culture systems. Techniques will be developed to detect production of small amounts of virus-specific antigens by the persistent infection, especially at the time reactivation has been attempted by superinfection with heterotypic helper virus. Because of the nature of the influenza virus genome it seems likely that recombination may occur in such a system so that persistent infection may also serve as a repository of genetic information for the virus. The site of persistent infections is unknown but will also be investigated. In particular, the ability of influenza to persist in lymphocytes is of interest. It is known that many RNA viruses persist, in lymphocytes in a repressed state and replicate only when the host lymphocyte undergoes mitogenesis. It is proposed that such a mechanism might also operate for influenza virus infections and account for many of the phenomena associated with this virus. Specifically, reactivation induced by subsequent infection with a new sub-type might enable the persistent infection to replicate or express certain antigens anew, resulting in an anammestic antibody response by the host. That is, "original antigenic sin" characteristic of repeat infection with influenza, would be duplicated.